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Disease Associations of XMRV and MLV-Related Viruses
Judy A. Mikovits, PhD, Whittemore Peterson Institute for Neuro-Immune Disease
A new human retrovirus first associated with QQ variant RNaseL a gene in the hereditary prostate cancer gene locus, in prostate cancer in 2006. Detection of integration sites in unmanipulated prostate tissue; demonstration of neutralizing antibody and in situ hybridization for XMRV, supports XMRV as a human retroviral infection associated with prostate cancer. Although in the absence of direct sequencing it cannot be rule out the reactivity can be to related MLV viruses. In 2009 using a classical virology approach of viral isolation and transmission, electron micropscopy, serology and PCR, Lombardi et al demonstrated the first isolation of XMRV from blood from patients with chronic fatigue syndrome (CFS) predominately from the west coast of the United States. In 2010, Lo et al. extended these studies by detecting nucleic acids of MLV-related variants in the peripheral blood mononuclear cells of CFS from the northeastern United States suggesting additional strains capable of infecting humans exist. In a study of 300 CFS patients, 13developed lymphoproliferative disorders. Of those tested, 11/11 were positive for XMRV and 9/9 positive for clonalTCR gamma rearrangements. Spontaneous development of four immortalized B cells lines occurred during culture of cells from CFS patients. Three developed from B cells isolated from the peripheral blood (two of whom had B cell lymphoma) and one from a bone marrow biopsy. The B cell lineshave a mature CD20+, CD23+ phenotype and produce infectious XMRV. Virus production occurred despite extensive hypermutation of the proviruses in these cells by APOBEC3G. Therefore, XMRV infection may accelerate the development of B cell malignancies by either indirect chronic stimulation of the immune system and/or by direct infection of the B-cell lineage. Since viral load in peripheral blood is low, these data suggest that B cells in tissues such as spleen and lymph nodes could be an in vivo reservoir for XMRV. We have also identified an inflammatory cytokine and chemokine signature that distinguishes XMRV infected CFS patients from healthy controls with 94% sensitivity and specificity Monitoring immune dysfunction affords the opportunity to begin to understand the pathogenesis of XMRVs. In addition to these data, recent advances in developing tests for detection and characterization of XMRV–variants will be also be discussed